Identification of bone marrow cell subpopulations associated with improved functional outcomes in patients with chronic left ventricular dysfunction: An embedded cohort evaluation of the FOCUS-CCTRN trial

Doris A. Taylor, Emerson C. Perin, James T. Willerson, Claudia Zierold, Micheline Resende, Marjorie Carlson, Belinda Nestor, Elizabeth Wise, Aaron Orozco, Carl J. Pepine, Timothy D. Henry, Stephen G. Ellis, David X M Zhao, Jay H. Traverse, John P. Cooke, Robert C. Schutt, Aruni Bhatnagar, Maria B. Grant, Dejian Lai, Brian H. JohnstoneShelly L. Sayre, Lem Moyé, Ray F. Ebert, Roberto Bolli, Robert D. Simari, Christopher R. Cogle

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

In the current study, we sought to identify bone marrow-derived mononuclear cell (BM-MNC) subpopulations associated with a combined improvement in left ventricular ejection fraction (LVEF), left ventricular endsystolic volume (LVESV), and maximal oxygen consumption (VO2 max) in patients with chronic ischemic cardiomyopathy 6 months after receiving transendocardial injections of autologous BM-MNCs or placebo. For this prospectively planned analysis, we conducted an embedded cohort study comprising 78 patients from the FOCUS-Cardiovascular Cell Therapy Research Network (CCTRN) trial. Baseline BM-MNC immunophenotypes and progenitor cell activity were determined by flow cytometry and colony-forming assays, respectively. Previously stable patients who demonstrated improvement in LVEF, LVESV, and VO2 max during the 6-month course of the FOCUS-CCTRN study (group 1, n = 17) were compared to those who showed no change or worsened in one to three of these endpoints (group 2, n = 61) and to a subset of patients from group 2 who declined in all three functional endpoints (group 2A, n = 11). Group 1 had higher frequencies of B-cell and CXCR4+ BM-MNC subpopulations at study baseline than group 2 or 2A. Furthermore, patients in group 1 had fewer endothelial colony-forming cells and monocytes/macrophages in their bone marrow than those in group 2A. To our knowledge, this is the first study to show that in patients with ischemic cardiomyopathy, certain bone marrow-derived cell subsets are associated with improvement in LVEF, LVESV, and VO2 max at 6 months. These results suggest that the presence of both progenitor and immune cell populations in the bone marrow may influence the natural history of chronic ischemic cardiomyopathy—even in stable patients. Thus, it may be important to consider the bone marrow composition and associated regenerative capacity of patients when assigning them to treatment groups and evaluating the results of cell therapy trials.

Original languageEnglish (US)
Pages (from-to)1675-1687
Number of pages13
JournalCell transplantation
Volume25
Issue number9
DOIs
StatePublished - 2016

Bibliographical note

Funding Information:
This work was supported by the National Heart, Lung, and Blood InstituteNHLBI under cooperative agreement 5 UM1 HL087318, and also, in part, by the National Heart, Lung, and Blood Institute NHLBI by contracts N01 HB 37164 and HHSN268201000008C, which were awarded to the Molecular and Cellular Therapeutics Facility, University of Minnesota, and by contracts N01 HB 37163 and HHSN268201000007C, which were awarded to the Cell Processing Facility, Baylor College of Medicine. Further funding was provided by the National Center for Research Resources CTSA grant UL1 TR000064 awarded to the University of Florida. Funding from the Texas State Legislature was also used to assist investigators at the Texas Heart Institute, Houston, Texas. The CCTRN acknowledges its industry partners, Biosafe, Biologics Delivery System Group, and Cordis Corporation, for their contributions of equipment and technical support during the conduct of the trial. We also acknowledge Dr. Sonia Skarlatos (1953?2013) for her insight, expertise, and support of the CCTRN, which continues to propel the cell therapy field forward. In addition, we thank Dr. Ke Li of the Texas Heart Institute for creation of the heat map. The opinions expressed in this report do not necessarily reflect those of the National Heart, Lung, and Blood Institute, the NIH, or the US Department of Health and Human Services. The authors declare no conflicts of interest.

Publisher Copyright:
© 2016 Cognizant, LLC.

Keywords

  • Bone marrow
  • Cell therapy
  • Heart failure
  • Ischemic cardiomyopathy
  • Stem cells

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